Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells.

Abstract

A large number of studies have indicated that the activation of T helper cells for both antibody (1-6) and cytolytic T lymphocyte (CTL) 1 (7-11) 2 responses is restricted by products of the I region of the major histocompatibility complex (MHC), while the activation of CTL themselves is restricted by products of the K/D regions of the MHC (12-14). However, it is less clear how and when during their developmental pathway T ceils acquire their MHC-restricted self-recognition specificity. Studies with chimeras (12, 15, 16) and thymus-grafted nude mice (17, 18) have indicated that the MHC phenotype of the thymus dictates the particular MHC determinants that T cells recognize as self-recognition elements. In addition, the MHC phenotype of the extra-thymic environment has been implicated in the process that determines the restriction specificities of T cells (11,14,17,19,20). In vivo manipulation of the expression of MHC products may yield a better understanding of how the host environment (thymic or extra-thymic) determines restriction specificities of T ceils. One approach to achieving such manipulation is by in vivo administration of antibodies (Ab) to MHC products. A few reports describe the effect of in vivo anti-Ia Ab (5, 21-26) but no data on actual expression of I region products in the recipients are so far available. A recent report described suppression of B lymphocyte development in mice injected from birth with monoclonal anti-I-A Ab (27), i.e., surface Ia +, IgM ÷, and IgD ÷ B ceils did not develop in such mice.The purpose of the present study was to determine whether such chronic administration of anti-Ia Ab into mice during their first weeks of life might influence their T cell self-recognition repertoire. We show here that chronic injection of anti-I-A k Ab, starting in neonatal H-2 k mice, abrogates their ability to generate alloreactive and trinitrophenyl (TNP)-specific splenic CTL responses. Different mechanisms for this

Functional and Phenotypic Evidence for Presentation of Eα52–68 Structurally Related Self-Peptide(s) in I-Eα-Deficient Mice

“…It was previously reported that a pan-specific mAb directed at MHC class II molecules could inhibit the process of positive selection (19,20). Here, we report that an mAb directed at the complex of a self-peptide bound to self-MHC class II molecules can specifically interfere with the process of intrathymic negative selection in vivo.…”

“…Pioneering experiments using injection of anti-MHC class II mAbs into neonatal mice revealed that the development of MHC class II-restricted T cells requires their interaction with MHC class IIpositive cells in the thymus, and interference with this process has profound effects on T cell development (19). In these mice the lymphoid organs were devoid of CD8 Ϫ CD4 ϩ T cells, whereas the development of CD8 ϩ CD4 Ϫ T cells proceeded normally (20).…”

Idiotypic Regulation of T Cells in Graft‐Versus‐Host Disease and Autoimmunity

“…In fact, the evidence seems very clear that clones of T cells are actually selected positively for self-reactivity during an early differentiation step in the thymus cortex (Bevan 1977, Zinkernagel 1978, giving rise to a peripheral pool of T cells biased in favor of recognizing antigenic molecules in association with MHC allelic products to which they were exposed during their ontogeny in the thymus. At this point, it also seems clear that the specific interaction occurring during positive selection in the thymus involves the T-cell receptor complex, the CD4 and CD8 accessory molecules and thymic MHC antigens (Kruisbeeck et al 1983, McDuffie et al 1986. It is this step which seems to determine the differentiation of immature CD4+8+ thymocytes into more mature CD4+8-and CD4-8+ T cells (Teh et al 1988, Sha et al 1988.…”

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

“…Interaction of precursor T cells with H-2 Iabearing cells appears to be necessary for appropriate maturation of T helper cells. This, especially, suggests that thymic selection concerns class II MHC specifically (46,47). Indeed, the presence of class II (but not class I) MHC antigens on the cortical epithelium (48, 49) might suggest selection for class IIreactive cells.…”